ABSTRACT ST segment myocardial infarction (STEMI) is a serious acute coronary condition that affects 500,000 Americans each year and results in significant U.S. healthcare costs ($31B/year for acute MI treatment). STEMI mortality directly relates to the extent of the total myocardial injury and even with the ?gold standard? of reperfusion, up to 50% of the total myocardial injury can be related to reperfusion injury (RI) that occurs directly following the restoration of blood flow to the ischemic myocardium. Mild hypothermia (MH ? temperature ~ 34C) provides cardioprotection and may greatly diminish RI by reducing myocardial metabolic demand, free radical creation, and total infarct size. However, MH and all other current therapy options (pharmacologics, etc.) have been largely unsuccessful in the treatment of RI. This is due to the fact that the arterial obstruction does not allow for therapy delivery to the region of interest until PCI is completed, which would be too late to prevent RI. To address this limitation, we have developed and validated a novel, catheter-based method of selective auto-retroperfusion (SARP) that regulates the pressure to the venous system (<50mmHg) to locally deliver cooled arterial blood (MH-SARP) to the ischemic region. Importantly, results from our phase I studies have demonstrated remarkable and unprecedented reduction in infarct size (~93%) in a swine model of anterior LV MI which corresponded with an attenuation of markers for ischemic (cardiac troponin), reperfusion (ST segment depression) and cellular injury (oxygen, glucose and lactate uptake as well as caspase-3 expression). Interestingly, SARP alone also significantly (83%) reduced these indices to near equivalent levels suggesting that the primary benefit may be derived by oxygen delivery without the need for MH. In order to advance these outstanding proof of concept results towards a first in human, however, the SARP +/- MH therapeutic approach and mechanism must be critically challenged under more extensive, clinically translational conditions. In particular, the therapy must remain effective during longer ischemic and shorter retroperfusion periods while minimizing disruption to clinical workflow, door to balloon time, and overall risk to patients. Accordingly, the logical extension of the findings obtained during phase I are addressed by the following specific aims: 1) Chronic Animal Studies: to determine feasibility and integration into clinical workflow in a chronic model of anterior LV STEMI; and 2) Safety studies for Pre-IDE Submission: To obtain GLP data, and prepare Pre-IDE submission package for first in man. This Phase II study addresses a highly significant national and worldwide clinical need for reducing RI in STEMI patients and has the ability to reach across various NIH Institutes and Centers including the NIDDK and NHLBI.